Should anticancer drug doses be adjusted in the obese patient?

Selecting drug doses can be a challenging decision for the clinician when treating a patient with cancer who is significantly overweight. If total body weight is used to determine body surface area, calculated doses can be as much as 25%-30% higher than if ideal body weight is used, with the potential for severe toxicity {12). In the absence of dosing guidelines, some oncologists calculate doses based on ideal body weight, others use an average of ideal body weight and total body weight, and some use total body weight. Despite the potential importance of this decision, few studies (3-5) have investigated the effects of obesity on anticancer drug disposition, providing a remarkably scant database to use as a basis for individualized dosing. Traditionally, anticancer drug doses have been standardized to body surface area or body weight. This practice is based on relationships that exist between body size (e.g., total body weight and body surface area) and physiologic functions (e.g., cardiac output, liver or renal blood flow, and glomerular filtration rate) (6,7). The body surface area is particularly useful for scaling between species or between infants and adults. The goal of dose standardization is to produce consistent systemic drug exposure (e.g., area under the curve for drug concentration x time). In obese patients, however, it is difficult to obtain an accurate estimate of body surface area for drug dose normalization. As previously addressed (8), the nomogram most commonly used in clinical practice to estimate body surface area was devised from only nine non-obese individuals whose weights ranged from 25 kg to 90 kg. The usefulness of normalizing anticancer drug doses to body surface area in adults has been questioned by Grochow et al. (9). A retrospective analysis of more than 300 patients and nine anticancer agents showed that normalization of doses to body surface area, weight, or height was of minimal clinical value in achieving consistent drug exposure. The physiologic changes that occur in obese individuals and their effects on drug disposition have been reviewed by several authors (10-12). Physiologic changes that may alter drug distribution and elimination in the obese include increased blood volume, cardiac output, lean body mass, organ size, and adipose tissue mass. An increase in the volume of distribution (Vd) of lipid-soluble drugs is the primary observation seen clinically in the obese. Changes in plasma protein concentrations in obese individuals may affect free drug concentrations: albumin and total protein appear unchanged, but a racid glycoprotein, the major protein to which basic drugs bind, is increased in the obese. Consequently, a smaller free fraction may result in reduced drug effect. The effects of obesity on hepatic metabolism have not been fully characterized. Various drugs that undergo phase I metabolism (i.e., oxidation, reduction, and hydrolysis) have demonstrated either increased or unchanged drug clearance in obese subjects. Drugs that undergo the phase II metabolic reactions of glucuronidation and sulfation consistently show enhanced drug elimination. Studies investigating the influence of obesity on hepatic metabolism have not, however, included patients who have other underlying reasons for altered hepatic function, such as those that may be imposed by malignancy. Glomerular filtration and tubular secretion are increased in obese individuals compared with those in non-obese patients, resulting in higher clearances for drugs that are primarily renally eliminated. For many drugs, it appears clearance is actually increased in obese patients. Taken together, these observations suggest strongly that a more detailed knowledge of the effects of obesity on the pharmacologic behavior of anticancer agents is necessary to ensure appropriate drug therapy. The narrow therapeutic window that exists for many of these agents makes the establishment of dosing guidelines based on sound pharmacologic and toxicologic information a necessary step to assume effective drug exposure is achieved and toxicity is minimized. Few studies (3-5) have investigated the effects of obesity on the disposition of anticancer agents. Powis et al. (3) studied the effects of body weight on the pharmacokinetics of cyclophosphamide in 16 breast cancer patients. Of these patients, seven were obese (20%-30% over ideal body weight), and five were severely obese (l>30% over ideal body weight). Obese patients had lower drug clearance normalized to ideal body weight and body surface area, but there was no significant correlation between body weight and either total clearance or clearance normalized to total body weight. Unfortunately, although this study attempted to address an important question, dosing guidelines for cyclophosphamide in the obese patient cannot be inferred because of the small numbers of patients and the fact that only the inactive pro-drug was measured. Lind et al. (4) studied the pharmacokinetics of ifosfamide in 16 patients, including four obese patients (29%-50% over ideal body weight). They found no difference in clearance (total or normalized to total body weight and ideal body weight) between obese and normal patients. They did, however, find a significant increase in Vd (total and normalized for ideal body weight). Rodvold et al. (5) investigated the effects of obesity on the pharmacokinetics of doxorubicin and its metabolite, doxorubicinol, in 21 patients.